Despite documentation that HIV-1 is able to infect the developing fetus in utero in some cases, substantial data on how the virus is able to cross the placental barrier is lacking. An animal model would be useful for the determination of the viral and host factors involved in the infection of the developing fetus. The work outlined in this proposal focuses on the hypothesis that using the simian counterpart to HIV-1, SlVmac, infection of the fetus is associated with specific viral and host parameters. Specifically, to test this hypothesis and to develop a model system to study lentiviral infection of the developing fetus, we plan to: 1) determine the conditions necessary for the productive infection of placental cells in vitro with both HIV-1 and SlVmac, using both Hofbauer and trophoblast cell cultures and viral phenotypes with differing cellular tropisms, 2) study if exogenous factors, such as endotoxin, opiates, or specific immunoregulatory cytokines, influence growth of specific AIDS viruses in placental cell cultures, 3) determine the viral and clinical parameters associated with infection of the fetus by infecting monkeys with pathogenic cloned SlVmac viruses having varying cellular tropisms and studying the clinical parameters of the dams and infective status of the offspring, and 4) determine the mechanisms by which viruses are able to cross the placental barrier by a detailed study of placental tissue and characterization of the viral isolates obtained from the fetus and placenta.